Chronic pain represents a major health and economic problem throughout the world.
Despite major advances in understanding the physiological and pathological basis of pain, an ideal analgesic is yet to be discovered. Among analgesic drugs, the opioid class of compounds still remains the effective treatment agents for severe and chronic pain. For instance, see Parrot, Using opioid analgesic to manage chronic non-cancer pain in primary care, J. Am. Board Fam. Pract, 1999, 12, 293-306 and Cherny, New strategies in opioid therapy for cancer pain, J. Oncol. Manage 2000, 9, 8-15.
The existence of three opioid receptor types, mu opioid receptors (MOR), delta opioid receptor (DOR) and kappa opioid receptor (KOR) has been clearly established and is confirmed by cloning of these three receptors from mouse, rat, and human cDNAs. Along these lines, see Dhawan et al., International Union of Pharmacology. XII. Classification of Opioid Receptors, Pharmacol. Rev. 1996, 48, 567-592; and McCurdy et al., Opioid Receptor Ligands. In Burger's Medicinal Chemistry, Drug Discovery and Development, 7th ed.; Abraham et al., Eds. John Wiley & Sons: New York, N.Y., 2010.
All three opioid receptor types are located in the human central nervous system and each has a role in the mediation of pain. Morphine and related opioids currently prescribed as potent analgesics for the treatment of pain produce their analgesic activity primarily through their agonist action at the mu opioid receptors. The general administration of these medications is limited by significant side effects such as respiratory depression, muscle rigidity, emesis, constipation, tolerance, and physical dependence. For example, see Duthie, Adverse Effects of Opioid Analgesic Drugs, Br. J. Anaesth. 1987, 59, 6177 and van Ree et al., Opioids, Reward and Addiction: An Encounter of Biology, Psychology, and Medicine. Pharmacol. Rev. 1999, 51, 341-396.
A large body of evidence indicates the existence of physiological and functional interactions between mu and delta receptors. Ligands with agonist or antagonist action at the delta receptor, for example, have been shown to modulate the analgesic and adverse effects of mu agonists. See, for instance, Traynor et al., Delta opioid receptor subtypes and cross-talk with mu receptors. Trends Pharmacol. Sci. 1993, 14, 84-86; Rothman et al., Allosteric Coupling Among Opioid Receptors: Evidence for an Opioid Receptor Complex, In Handbook of Experimental Pharmacology, Volume 104, Opioid I; Hertz et al., Eds; Springer-Verlag; Berlin, 1993; pp. 217-237; Jordan et al., G-Protein-coupled receptor heterodimerization modulates receptor function. Nature 1999, 399, 697-700; George et al., Oligomerization of mu and delta Opioid Receptors, J. Biol. Chem. 2000, 275, 26128-26135; Levac et al., Oligomerization of opioid Receptors: Generation of novel signaling units, Curr. Opin. Pharmacol., 2002, 2, 76-81.
On the other hand, agonist action at the delta receptors potentiate mu receptor mediated analgesic effects and antagonist action at the delta receptor suppresses the tolerance, physical dependence, and related side effects off mu agonists without affecting their analgesic activity. In a study using the nonpeptide ligand naltrindole, Abdelhamid et al. demonstrated that the delta receptor antagonist greatly reduced the development of morphine tolerance and dependence in mice in both the acute and chronic models without affecting the analgesic actions of morphine. See Abdelhamid et al., Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J. Pharmacol. Exp. Ther. 1991, 258, 299-303. Fundytus et al., reported that continuous infusion of the delta selective antagonist TIPP[Ψ] by the intracerbroventricular (icv) route in parallel with continuous administration of morphine by the subcutaneous route to rats attenuated the development of morphine tolerance and dependence to a large extent. See Fundytus, et al., Attenuation of morphine tolerance and dependence with the highly selective delta-opioid receptor antagonist TIPP[Ψ]. Eur. J. Pharmacol 1995, 286, 105-108.
Schiller et al., found that the peptide ligand DIPP-NH2[Ψ] displayed mixed mu agonist/delta antagonist properties in vitro and that the compound given icv produced analgesic effect with no physical dependence and less tolerance than morphine in rats. See Schiller et al., Four different types of Opioid Peptides with mixed mu agonist/delta Antagonist Properties Analgesia 1995, 1, 703-706; and Schiller et al., The Opioid mu agonist/delta antagonist DIPP-NH2-[Ψ] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats, J. Med. Chem. 1999, 42, 3520-3526.
Studies with antisense oligonucleotides of delta receptors have demonstrated that reduction of receptor expression diminishes the development and/or expression of morphine dependence without compromising antinociception produced by mu agonists. See Suzuki et al., Antisense oligodeoxynucleotide to delta opioid receptors attenuates morphine dependence in mice, Life Sci. 1997, 61, PL 165-170; and Sanchez-Blazquez et al., Antisense oligodeoxynucleotides to opioid mu and delta receptors reduced morphine dependence in mice: Role of delta-2 opioid receptors, J. Pharmacsol. Exp. Ther. 1997, 280, 1423-1431. Furthermore, genetic deletion studies using delta receptor knockout mice have shown that these mutant mice retain supraspinal analgesia and do not develop analgesic tolerance to morphine. Zhu et al., Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice, Neuron, 1999, 24, 243-252.
Discovery of nonpeptide opioid ligands possessing a balanced profile of mixed mu agonist/delta antagonist activity has been a challenge. In an early study focusing on naltrexone-derived heterocycle annulated morphinan ligands, it was found that compounds arising by fusion of a heteroaromatic ring such as a pyridine ring on the C5-C6 of the C-ring gave pyridomorphinans that displayed high affinity binding at the opioid receptors. The binding affinity and functional activity are modulated by the substituents placed at the 5′-position on the pyridine moiety. For example, the introduction of aromatic groups such as a phenyl group or a 1-pyrrolyl group at this position gave ligands with high binding affinity and improved antagonist potency as determined in bioassays using mouse vas deferens smooth muscle preparations. See Ananthan et al., Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans, J. Med. Chem. 1999, 42, 3527-3538; and Ananthan et al., Synthesis, opioid receptor binding, and functional activity of 5′-substituted 17-cyclopropylmethylpyrido[2′,3′:6,7]morphinans. Bioorg. Med. Chem. Lett. 2003, 13, 529-532.
Interestingly, among phenyl ring substituted analogues, the p-chlorophenyl compound displayed a mixed mu agonist/delta antagonist profile of activity in the smooth muscle assays in vitro. In analgesic activity evaluations, this compound displayed partial agonist activity in the tail-flick assay and a full agonist activity in the acetic acid writhing assay after icv or ip administration in mice, and it did not produce tolerance to antinociceptive effects on repeated ip injections. Studies in mice with selective antagonists, characterized this compound as a partial mu agonist/delta antagonist. See Wells et al., In Vivo Pharmacological Characterization of SoRI 9409, a Nonpeptidic opioid mu-agonist/delta-antagonist that produces limited antinociceptive tolerance and attenuates morphine physical dependence. J. Pharmacol. Exp. Ther. 2001, 297, 597-605. In in vitro biochemical assays using [35S]GTP-γ-S binding, this compound, however, failed to display mu agonist activity in guinea pig caudate membranes as well as in cloned cells expressing human mu receptors. See Xu et al., SoRI-9409, a Non-peptide opioid mu receptor agonist/delta receptor antagonist, fails to stimulate [35S]-GTP-γ-S binding at cloned opioid receptors. brain res. bull. 2001, 55, 507-511. A similar pyridine annulations strategy when applied to oxymorphone and hydromorphone frameworks led to ligands that displayed mixed mu agonist/delta antagonist activity although with somewhat weak mu agonist potency. See Ananthan et al., Identification of ligands possessing mixed μ agonist/δ antagonist activity among pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone. J. Med. Chem. 2004, 47, 1400-1412.
Bivalent ligands possessing a mu agonist unit such as oxymorphone tethered to a delta antagonist unit such as naltrindole by a 16 to 21 atom chain have been investigated as ligands targeting mu-delta heterodimers. Among such compounds, bivalent ligand whose spacer was 16 atoms or longer produced less dependence than morphine; ligands possessing spacer lengths of 19 atoms or greater produced less physical dependence and tolerance. See Daniels et al., Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 19208-19213.
Schmidhammer and coworkers explored a number of morphinans possessing an alkoxy substituent at the 14-position. The morphinan templates explored include 6-oxomorphinans, 6-aminomorphinans, indolomorphinans and benzofuromorphinans. Depending upon the template and the substituents, compounds with varying profiles were obtained. See Schmidhammer, et al., Synthesis and biological evaluation of 14-alkoxymorphinans. 4. Opioid agonists and partial opioid agonists in a series of N-(cyclobutylmethyl)-14-methoxymorphinan-6-ones. Helv. Chim. Acta 1989, 72, 1233-1240; Schmidhammer et al., Synthesis and biological evaluation of 14-alkoxymorphinans. 1. Highly potent opioid agonists in the series of (−)-14-methoxy-N-methylmorphinan-6-ones. J. Med. Chem. 1984, 27, 1575-1579; Schmidhammer et al. Synthesis and biological evaluation of 14-alkoxymorphinans. (−)-N-(cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one, a selective mu opioid receptor antagonist. J. Med. Chem. 1989, 32, 418-421; Schmidhammer et al., Opioid Receptor Antagonists. Elsevier: New York, 1998; pp. 83-132; Schmidhammer, et al., 14-Alkoxymorphinans-A series of highly potent opioid agonists, antagonists, and partial agonists. Curr. Top. Med. Chem. 1993, 1, 261-276. Some of the compounds especially those derived from 6-oxomorphinans with 3-phenylpropoxy group at the 14-position were very potent nonselective opioid agonists with no measurable antagonist activity. See Greiner et al., Synthesis and biological evaluation of 14-alkoxymorphinans. 18. N-substituted 14-phenylpropyloxymorphinan-6-ones with unanticipated agonist properties: extending the scope of common structure-activity relationships. J. Med. Chem. 2003, 46, 1758-1763; Lattanzi et al. Synthesis and biological evaluation of 14-alkoxymorphinans. 22. (1) Influence of the 14-alkoxy group and the substitution in position 5 in 14-alkoxymorphinan-6-ones on in vitro and in vivo activities. J. Med. Chem. 2005, 48, 3372-3378.
There have been suggestions that antagonists at MOR, DOR and KOR are potentially useful as immunosuppressants, anti-allergic and anti-inflammatory agents and as treatment agents for addiction, drug abuse, alcoholism, obesity and a variety of neurological diseases. See Schmidhammer et al., Opioid Receptor Antagonists. Elsevier: New York, 1998; pp. 83-132.